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In the transition from childhood to adulthood there is a reversal in the sex distribution of asthma from a male predominance to a female predominance. Studying these sex differentials may contribute to our understanding of the processes that initiate and perpetuate disease. In a matched case control study the OR of asthma in the offspring of mothers who used the oral contraceptive pill (OCP) prior to pregnancy was 1.16 (95% CI 1.06, 1.27). These were predominantly female, under three year’s old, non-atopic and not receiving medication for asthma. In a cohort study of 223, higher oestrogen levels in late pregnancy were associated with higher IFN-γ production in cord blood cells and a reduced risk of wheezing in the first 6 months of life only. In surveys of children aged 9-11 from 1989 to 2004 the male to female ratio narrowed significantly for wheeze (1.34 to 0.98:1 p<0.0002), asthma (1.74 to 1.02:1 p<0.0001), eczema (1.42:1 to 0.81:1 p<0.0001) and hay fever (1.46 to 0.93:1 p<0.0001). In two whole population datasets covering UK (CMR and GPRD), sex specific presentations for asthma and allergic rhinitis peaked in early adolescence for females and later for males. Eczema presentations peaked in infancy in both sexes but females predominated from 15-49 years. In 9-11 year old children examined in 1989 males were more likely to have wheeze (OR 1.63; 95% CI 1.15, 2.23) and current asthma (OR 2.80; 95%CI 1.72, 4.56). Of the 711 participants followed 10 years later males were twice as likely to lose their childhood wheeze (OR 2.03; 95% CI 1.11, 3.72) and have significantly less BHR than females (OR 0.65; 95% CI 0.48, 0.89). Higher tertiles of testosterone was associated with a 50% reduction in the risk of BHR (OR 0.49; 95% CI 0.25, 0.93). This is an exciting area for future research.

Asthma is a complex obstructive airway disease characterised by airway hyper-reactivity to innocuous allergens. It may be categorised as either classical eosinophilic, T helper 2 type of disease or as one driven by neutrophils that may be associated with T helper 17 cells and that is corticosteroid resistant. While the pathogenesis of the disease is not fully understood, there is increasing evidence for the role of environmentally-derived pathogen-associated molecular patterns (PAMPs) including fungal β-(1,3)-glucans and bacterial lipopolysaccharide (LPS) in inducing and exacerbating airway inflammation. We investigated the effects of these components, either alone or in combination, in several models of pulmonary inflammation and discovered that they modified airway responses in vivo. Notably, a combination of PAMPs drove a profound neutrophilia that was associated with synergistic CCL5 production. Moreover, in allergic models using house dust mite, sensitisation with these agonists resulted in corticosteroid resistant airway hyper-responsiveness. Interestingly, we found severe asthmatics with corticosteroid resistant neutrophilia to have upregulated CCL5 mRNA levels when compared to moderate asthmatics or controls. Interactions of environmental PAMPs from multiple sources could present a key determinant in the development and pathogenesis of corticosteroid resistant asthma.

We have read with interest the article by Bedolla et al. [1] and we believe the lack of association between passive smoking and asthma might be a consequence of the way the variable was measured. They defined passive smoking as follows: “smoking was considered as passive when one or more cigarettes were consumed by one or by both parents in the presence of the children”. We would like to highlight some factors that could have been taken into count when defining this variable: time of smoking, frequency and number of cigarettes.

Exercise-induced bronchoconstriction (EIB) is the most common chronic medical condition affecting elite athletes; our understanding of the condition remains however incomplete. The over-arching aim of this thesis was therefore to investigate the underlying mechanisms of EIB in athletes. More specifically, via induced and inhibited bronchoconstriction, the influence of airway dehydration on bronchial hyper-responsiveness, epithelial injury and inflammatory mediator release was investigated. The results of our first experiment suggest that mild, whole-body dehydration does not affect the severity of EIB in athletes; however, signs of small airway dysfunction were noticed post-dehydration. The clinical and functional relevance of these findings are yet to be evaluated. Our next two experiments showed that administration of a single, therapeutic dose of the inhaled 32-agonist terbutaline before bronchial provocation challenge with dry air I) reduced the severity of bronchoconstriction by 54% in athletes, ii) attenuated the rise in urinary CC16 (a marker of airway epithelial injury), and iii) inhibited the release of the mast-cell derived broncho-constrictive mediator prostaglandin (PG)Dz. These results suggest that local airway dehydration and mast cell activation have a key role in hyperpnoea-induced epithelial injury and bronchoconstriction in athletes. In our final study, using a newly developed mass spectrometry platform, we identified for the first time that exercise provocation is not solely associated with the release of potent broncho-constrictive mediators, such as PGD2 and thromboxane, but also with the release of the broncho-protective mediators PGE2 and PGI2. These results of naturally occurring broncho-protective agents in response to exercise open exciting new opportunities for drug development for ElB.